Concordance Between Biochemical and Molecular Diagnosis Obtained by WES in Mexican Patients with Inborn Errors of Intermediary Metabolism: Utility for Therapeutic Management

Abstract

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management.

Keywords: diagnostic odyssey; genomic medicine; inborn errors of metabolism; personalized medicine; precision medicine; rare diseases; whole-exome sequencing.

Figure 1

Overall, WES diagnosis concordance of the entire study population and by study groups. Note that maximum concordance was reached for those patients bearing a well-defined biochemical phenotype (Group 1) for a specific IEiM (91.3%). Instead, only in 23.1% of patients bearing an unspecific biochemical alteration (Group 2) suggesting an underlying IEiM did WES achieve a diagnostic genotype of a specific IEiM. Abbreviations: IEiM, inborn errors of intermediary metabolism; WES, whole-exome sequencing; VUS, variant of uncertain significance; DBT, branched-chain acyl transferase E2 component; GALK1, galactokinase-1 deficiency; HLCS, holocarboxylase synthetase; ACADM, acyl-CoA dehydrogenase medium-chain.

Figure 2

Concordance between the initial biochemical diagnosis and WES results performed in 95 patients by type of disorder: (A) total, (B) Group 1, and (C) Group 2. Biochemically confirmed or suspected IEiM categories in the studied population by type of IEiM and by group before (light bars) and after WES (dark bars) in the overall study population (D), Group 1 (E), and Group 2 (F). Concordance⁺ between the initial and final diagnoses is the degree to which the initial biochemical diagnosis matches the final molecular diagnosis. Abbreviations: UCD, urea cycle disorders; OA, organic acid disorders; AA, amino acid disorders; CARB, carbohydrate disorders; LIPID, lipid defects. A p-value < 0.05 was considered to be statistically significant (* p < 0.05, ** p < 0.01, and **** p < 0.0001, ns: not statistically significant).

Figure 3

WES-positive IEiM landscape found in the studied Mexican patients. Abbreviations:CoA: coenzyme A; Def: deficiency; HHH Sx: hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; MCAD: medium-chain acyl-CoA dehydrogenase deficiency, MSUD: maple syrup urine disease; OTC: ornithine transcarbamylase.